tbuckley/cabot-search huggingface dataset:
GeneSegNet: a deep learning framework for cell segmentation by integrating gene expression and imaging
Authors: Yuxing Wang, Wenguan Wang, Dongfang Liu, Wenpin Hou, Tianfei Zhou, Zhicheng Ji
Journal: Genome biology (2023)

When analyzing data from in situ RNA detection technologies, cell segmentation is an essential step in identifying cell boundaries, assigning RNA reads to cells, and studying the gene expression and morphological features of cells. We developed a deep-learning-based method, GeneSegNet, that integrates both gene expression and imaging information to perform cell segmentation. GeneSegNet also employs a recursive training strategy to deal with noisy training labels. We show that GeneSegNet significantly improves cell segmentation performances over existing methods that either ignore gene expression information or underutilize imaging information.
Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms
Authors: Manling Xie, Praveen N. Pallegar, Sebastian Parusel, Aivi T. Nguyen, Long-Jun Wu
Journal: Molecular Neurodegeneration (2023)

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.
<i>QuickStats:</i> Rate* of Emergency Department Visits,† by Homeless Status§ — National Hospital Ambulatory Medical Care Survey, United States, 2010–2021
Authors: Loredana Santo
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Persons experiencing homelessnessPersons not experiencing homelessness Years * Visit rates are based on estimates of the U.S. population experiencing homelessness, reported by the U.S.Department of Housing and Urban Development, from data collected on a single night in January of each year during 2010-2021.The estimate for 2021 was adjusted for incompleteness.Visit rates for the population not experiencing homelessness are based on estimates of the U.S. civilian, noninstitutionalized population developed by the U.S. Census Bureau and reflect the population as of July 1 of each year during 2010-2021.† Based on a sample of visits to emergency departments in noninstitutional general and short-stay hospitals, exclusive of federal, military, and Veterans Administration hospitals, located in U.S. states and the District of Columbia.§ Persons experiencing homelessness are identified as having no home or living in a homeless shelter.Persons not experiencing homelessness are identified as having a private residence, living in a nursing home, or having some other living arrangement.Patient residence was missing for 3.0% of emergency department visits; these records were excluded from the analysis.The rate of visits to hospital emergency departments by persons experiencing homelessness increased from an estimated 141 visits per 100 persons per year during 2010-2011 to 310 during 2020-2021.Rates increased during 2016-2017 compared with 2014-2015, and again during 2020-2021 compared with 2018-2019.Visit rates for persons not experiencing homelessness did not vary significantly across years, ranging from 42 visits per 100 persons per year during 2010-2011 to 40 during 2020-2021.Visit rates for persons experiencing homelessness were higher than rates for persons not experiencing homelessness in all years.
Characterization of the responses of brain macrophages to focused ultrasound-mediated blood–brain barrier opening
Authors: Alina R. Kline-Schoder, Sana Chintamen, Moshe J. Willner, Melody R. DiBenedetto, Rebecca L. Noel, Alec J. Batts, Nancy Kwon, Stergios Zacharoulis, Cheng-Chia Wu, Vilas Menon, Steven G. Kernie, Elisa E. Konofagou
Journal: Nature Biomedical Engineering (2023)
Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease
Authors: Chia-Chen Liu, Na Wang, Yuanxin Chen, Yasuteru Inoue, Francis Shue, Yingxue Ren, Minghui Wang, Wenhui Qiao, Tadafumi C. Ikezu, Zonghua Li, Jing Zhao, Yuka Martens, Sydney V. Doss, Cassandra L. Rosenberg, Suren Jeevaratnam, Lin Jia, Ana-Caroline Raulin, Fangfang Qi, Yiyang Zhu, Alla Alnobani, Joshua Knight, Yixing Chen, Cynthia Linares, Aishe Kurti, John D. Fryer, Bin Zhang, Long-Jun Wu, Betty Y. S. Kim, Guojun Bu
Journal: Nature Immunology (2023)
Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry
Authors: P. Jane McDowell, Ron McDowell, John Busby, M. Chad Eastwood, Pujan H. Patel, David J. Jackson, Adel Mansur, Mitesh Patel, Hassan Burhan, Simon Doe, Rekha Chaudhuri, Robin Gore, James W. Dodd, Deepak Subramanian, Thomas Brown, Liam G. Heaney
Journal: European Respiratory Journal (2023)

Background Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. Methods This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 &lt;1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. Results 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73–31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45–0.93), obese (OR 0.49, 95% CI 0.24–0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12–0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76–0.97) for every 10-year increase in disease duration. 12–21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. Conclusions 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.
Dual spatially resolved transcriptomics for human host–pathogen colocalization studies in FFPE tissue sections
Authors: Hailey Sounart, Enikő Lázár, Yuvarani Masarapu, Jian Wu, Tibor Várkonyi, Tibor Glasz, András Kiss, Erik Borgström, Andrew Hill, Sefanit Rezene, Soham Gupta, Aleksandra Jurek, Anezka Niesnerová, Henrik Druid, Olaf Bergmann, Stefania Giacomello
Journal: Genome biology (2023)

Abstract Technologies to study localized host–pathogen interactions are urgently needed. Here, we present a spatial transcriptomics approach to simultaneously capture host and pathogen transcriptome-wide spatial gene expression information from human formalin-fixed paraffin-embedded (FFPE) tissue sections at a near single-cell resolution. We demonstrate this methodology in lung samples from COVID-19 patients and validate our spatial detection of SARS-CoV-2 against RNAScope and in situ sequencing. Host–pathogen colocalization analysis identified putative modulators of SARS-CoV-2 infection in human lung cells. Our approach provides new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes in FFPE samples.
Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice
Authors: Tiago L. Duarte, Marta Lopes, Mónica Oliveira, Ana G. Santos, Catarina Vasco, Joana P. Reis, Ana Rita Antunes, Andreia Gonçalves, Sérgio Chacim, Cláudia Oliveira, Beatriz Porto, Maria José Teles, Ana C. Moreira, André M. N. Silva, Ron Schwessinger, Hal Drakesmith, Rui Henrique, Graça Porto, Delfim Duarte
Journal: Leukemia (2023)
GoM DE: interpreting structure in sequence count data with differential expression analysis allowing for grades of membership
Authors: Peter Carbonetto, Kaixuan Luo, Abhishek Sarkar, Anthony Hung, Karl Tayeb, Sebastian Pott, Matthew Stephens
Journal: Genome biology (2023)

Parts-based representations, such as non-negative matrix factorization and topic modeling, have been used to identify structure from single-cell sequencing data sets, in particular structure that is not as well captured by clustering or other dimensionality reduction methods. However, interpreting the individual parts remains a challenge. To address this challenge, we extend methods for differential expression analysis by allowing cells to have partial membership to multiple groups. We call this grade of membership differential expression (GoM DE). We illustrate the benefits of GoM DE for annotating topics identified in several single-cell RNA-seq and ATAC-seq data sets.
A cluster randomised controlled trial to reduce respiratory effects of cotton dust exposure among textile workers: the MultiTex RCT study
Authors: Asaad Ahmed Nafees, Asad Allana, Muhammad Masood Kadir, James Potts, Cosetta Minelli, Sean Semple, Sara De Matteis, Peter Burney, Paul Cullinan
Journal: European Respiratory Journal (2023)

Background We determined the effectiveness of an intervention to reduce cotton dust-related respiratory symptoms and improve lung function of textile workers. Methods We undertook a cluster randomised controlled trial at 38 textile mills in Karachi, Pakistan. The intervention comprised: training in occupational health for workers and managers, formation of workplace committees to promote a health and safety plan that included wet mopping and safe disposal of cotton dust, provision of simple face masks, and further publicity about the risks from cotton dust. Participating mills were randomised following baseline data collection. The impact of the intervention was measured through surveys at 3, 12 and 18 months using questionnaires, spirometry and dust measurements. The primary outcomes were 1) changes in prevalence of a composite respiratory symptom variable, 2) changes in post-bronchodilator percentage predicted forced expiratory volume in 1 s (FEV 1 ) and 3) changes in cotton dust levels. These were assessed using two-level mixed effects linear and logistic regression. Results Of 2031 participants recruited at baseline, 807 (40%) were available at the third follow-up. At that point, workers in the intervention arm were more likely to report an improvement in respiratory symptoms (OR 1.58, 95% CI 1.06–2.36) and lung function (FEV 1 % pred: β 1.31%, 95% CI 0.04–2.57%). Personal dust levels decreased, more so in intervention mills, although we did not observe this in adjusted models due to the small number of samples. Conclusion We found the intervention to be effective in improving the respiratory health of textile workers and recommend scaling-up of such simple and feasible interventions in low- and middle-income countries.
CRISPR-Cas9 base editing of pathogenic CaMKIIδ improves cardiac function in a humanized mouse model
Authors: Simon Lebek, Xurde M. Caravia, Leon G. Straub, Damir Alzhanov, Wei Tan, Hui Li, John R. McAnally, Kenian Chen, Lin Xu, Philipp E. Scherer, Ning Liu, Rhonda Bassel-Duby, Eric N. Olson
Journal: Journal of Clinical Investigation (2023)

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage.
Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits
Authors: Yi-Jun Ge, Bang-Sheng Wu, Yi Zhang, Shi-Dong Chen, Ya-Ru Zhang, Ju-Jiao Kang, Yue-Ting Deng, Ya-Nan Ou, Xiao-Yu He, Yong-Li Zhao, Kevin Kuo, Qing Ma, Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Herve Lemaitre, Tomáš Paus, Luise Poustka, Sarah Hohmann, Sabina Millenet, Juliane H Fröhner, Michael N Smolka, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Jian-Feng Feng, Lan Tan, Qiang Dong, Gunter Schumann, Wei Cheng, Jin-Tai Yu
Journal: Nature Human Behaviour (2023)

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan. A genome-wide association study of cerebral ventricle phenotypes finds 62 unique loci and reveals a genetic overlap between ventricular and neuropsychiatric traits.
Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning
Authors: Maximilian J. Wessel, Elena Beanato, Traian Popa, Fabienne Windel, Pierre Vassiliadis, Pauline Menoud, Valeriia Beliaeva, Ines R. Violante, Hedjoudje Abderrahmane, Patrycja Dzialecka, Chang-Hyun Park, Pablo Maceira-Elvira, Takuya Morishita, Antonino M. Cassara, Melanie Steiner, Nir Grossman, Esra Neufeld, Friedhelm C. Hummel
Journal: Nature Neuroscience (2023)

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here we show successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, functional magnetic resonance imaging studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as an exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional role. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.
The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial
Authors: Jason J. Luke, Manish R. Patel, George R. Blumenschein, Erika Hamilton, Bartosz Chmielowski, Susanna V. Ulahannan, Roisin M. Connolly, Cesar A. Santa-Maria, Jie Wang, Shakeela W. Bahadur, Andrew Weickhardt, Adam S. Asch, Girish Mallesara, Philip Clingan, Monika Dlugosz-Danecka, Monika Tomaszewska-Kiecana, Halyna Pylypenko, Nada Hamad, Hedy L. Kindler, Bradley J. Sumrow, Patrick Kaminker, Francine Z. Chen, Xiaoyu Zhang, Kalpana Shah, Douglas H. Smith, Anushka De Costa, Jonathan Li, Hua Li, Jichao Sun, Paul A. Moore
Journal: Nature Medicine (2023)

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .
The rat frontal orienting field dynamically encodes value for economic decisions under risk
Authors: Chaofei Bao, Xiaoyue Zhu, Joshua Mōller-Mara, Jingjie Li, Sylvain Dubroqua, Jeffrey C. Erlich
Journal: Nature Neuroscience (2023)

Abstract Frontal and parietal cortex are implicated in economic decision-making, but their causal roles are untested. Here we silenced the frontal orienting field (FOF) and posterior parietal cortex (PPC) while rats chose between a cued lottery and a small stable surebet. PPC inactivations produced minimal short-lived effects. FOF inactivations reliably reduced lottery choices. A mixed-agent model of choice indicated that silencing the FOF caused a change in the curvature of the rats’ utility function ( U = V ρ ). Consistent with this finding, single-neuron and population analyses of neural activity confirmed that the FOF encodes the lottery value on each trial. A dynamical model, which accounts for electrophysiological and silencing results, suggests that the FOF represents the current lottery value to compare against the remembered surebet value. These results demonstrate that the FOF is a critical node in the neural circuit for the dynamic representation of action values for choice under risk.
A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS
Authors: Lisa Johann, Sasha Soldati, Kristin Müller, Josephine Lampe, Federico Marini, Matthias Klein, Eva Schramm, Nathalie Ries, Carsten Schelmbauer, Ilaria Palagi, Khalad Karram, Julian C. Assmann, Mahtab A. Khan, Jan Wenzel, Mirko H.H. Schmidt, Jakob Körbelin, Dirk Schlüter, Geert van Loo, Tobias Bopp, Britta Engelhardt, Markus Schwaninger, Ari Waisman
Journal: Journal of Clinical Investigation (2023)

A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20ΔCNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL to be expressed by A20-deficient CNS-ECs, which we found to function as adhesion molecules. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20ΔCNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in WT mice. In addition, blocking of ICOSL on primary mouse brain microvascular ECs impaired the adhesion of T cells in vitro. Taken together, we propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.